Similar to other yeasts, the human pathogen Candida glabrata ages when it undergoes asymmetric, finite cell divisions, which determines its replicative lifespan. We sought to investigate if and how aging changes resilience of C. glabrata populations in the host environment. Our data demonstrate that old C. glabrata are more resistant to hydrogen peroxide and neutrophil killing, whereas young cells adhere better to epithelial cell layers. Consequently, virulence of old compared to younger C. glabrata cells is enhanced in the Galleria mellonella infection model. Electron microscopy images of old C. glabrata cells indicate a marked increase in cell wall thickness. Comparison of transcriptomes of old and young C. glabrata cells reveals differential regulation of ergosterol and Hog pathway associated genes as well as adhesion proteins, and suggests that aging is accompanied by remodeling of the fungal cell wall. Biochemical analysis supports this conclusion as older cells exhibit a qualitatively different lipid composition, leading to the observed increased emergence of fluconazole resistance when grown in the presence of fluconazole selection pressure. Older C. glabrata cells accumulate during murine and human infection, which is statistically unlikely without very strong selection. Therefore, we tested the hypothesis that neutrophils constitute the predominant selection pressure in vivo. When we altered experimentally the selection pressure by antibody-mediated removal of neutrophils, we observed a significantly younger pathogen population in mice. Mathematical modeling confirmed that differential selection of older cells is sufficient to cause the observed demographic shift in the fungal population. Hence our data support the concept that pathogenesis is affected by the generational age distribution of the infecting C. glabrata population in a host. We conclude that replicative aging constitutes an emerging trait, which is selected by the host and may even play an unanticipated role in the transition from a commensal to a pathogen state.
A series of cases in the Northeast of the US during 2013–2015 described a new Borrelia species, Borrelia miyamotoi, which is transmitted by the same tick species that transmits Lyme disease and causes a relapsing fever-like illness. The geographic expansion of B. miyamotoi in the US also extends to other Lyme endemic areas such as the Midwestern US. Co-infections with other tick borne diseases (TBD) may contribute to the severity of the disease. On Long Island, NY, 3–5% of ticks are infected by B. miyamotoi, but little is known about the frequency of B. miyamotoi infections in humans in this particular region. The aim of this study was to perform a chart review in all patients diagnosed with B. miyamotoi infection in Stony Brook Medicine (SBM) system to describe the clinical and epidemiological features of B. miyamotoi infection in Suffolk County, NY. In a 5 year time period (2013–2017), a total of 28 cases were positive for either IgG EIA (n = 19) or PCR (n = 9). All 9 PCR-positive cases (median age: 67; range: 22–90 years) had clinical findings suggestive of acute or relapsing infection. All these patients were thought to have a TBD, prompting the healthcare provider to order the TBD panel which includes a B. miyamotoi PCR test. In conclusion, B. miyamotoi infection should be considered in the differential diagnosis for flu-like syndromes during the summer after a deer tick bite and to prevent labeling a case with Lyme disease.
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